Ultrahigh Enzyme Loading Metal-Organic Frameworks for Deep Tissue Pancreatic Cancer Photoimmunotherapy

Protein drugs hold promise in treating multiple complex diseases, including cancer. The priority of protein drug application is precise delivery of substantial bioactive protein into tumor site. Metal-organic-framework (MOF) is widely considered as a promising carrier to encapsulate protein drug owing to the noncovalent interaction between carrier and protein. However, limited loading efficiency and potential toxicity of metal ion in MOF restrict its application in clinical research. Herein, a tumor targeted collagenase-encapsulating MOF via protein-metal ion-organic ligand coordination (PMOCol) for refining deep tissue pancreatic cancer photoimmunotherapy is developed. By an expedient method in which the ratio of metal ion, histidine residues of protein and ligand is precisely controlled, PMOCol is constructed with ultrahigh encapsulation efficiency (80.3 wt%) and can release collagenase with high enzymatic activity for tumor extracellular matrix (ECM) regulation after reaching tumor microenvironment (TME). Moreover, PMOcol exhibits intensively poorer toxicity than the zeolitic imidazolate framework-8 biomineralized protein. After treatment, the pancreatic tumor with abundant ECM shows enhanced immunocyte infiltration owing to extracellular matrix degradation that improves suppressive TME. By integrating hyperthermia agent with strong near-infrared absorption (1064 nm), PMOCol can induce acute immunogenicity to host immunity activation and systemic immune memory production to prevent tumor development and recurrence. A tumor targeted collagenase-encapsulating metal-organic-framework (MOF) via protein-metal ion-organic ligand coordination (PMOCol) is developed for refining deep tissue pancreatic cancer photoimmunotherapy. The PMOCol demonstrates ultrahigh loading capacity (80.3%) and can effectively regulate extracellular matrix, which further enhances immunocyte infiltration for cancer immunotherapy. By integrating hyperthermia agent, PMOCol induces acute localized immunogenicity and systemic immune memory to prevent tumor development and recurrence.image

Automated summary

Protein drugs are potential candidates for treating complex diseases like cancer. Metal-organic-framework (MOF) is considered a promising carrier for encapsulating protein drugs, but its limited loading efficiency and potential toxicity hinder its clinical application. In this study, a tumor targeted collagenase-encapsulating MOF (PMOCol) is developed for refining deep tissue pancreatic cancer photoimmunotherapy. PMOCol demonstrates high encapsulation efficiency (80.3 wt%) and can effectively regulate extracellular matrix, enhancing immunocyte infiltration for cancer immunotherapy. By integrating a hyperthermia agent, PMOCol induces acute immunogenicity and systemic immune memory to prevent tumor development and recurrence.